DIPYRIDAMOLE ENHANCES RELAXATIONS AND cGMP GENERATION TO NITRIC OXIDE IN LAMBS WITH PERSISTENT PULMONARY HYPERTENSION (PPHN). • 2090

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We have previously shown that the cGMP specific phosphodiesterase inhibitor zaprinast enhances the effect of NO in lambs with PPHN (AJRCCM 1995; 152: 1605). We now studied the effect of an equimolar concentration of the commercially available phosphodiesterase inhibitor dipyridamole (DIP) on relaxations to sodium nitroprusside (SNP). Fourth generation pulmonary arteries were isolated from 5 near-term fetal lambs with PPHN following ligation of the ductus arteriosus 10 days prior to delivery and age matched controls. Vessels were submaximally preconstricted with norepinephrine (NE, 1μM) following pretreatment with indomethacin. Relaxations to increasing concentrations of SNP (1-1000 nM) were then compared in PA with and without pretreatment with dipyridamole (30 μM). Without DIP, there was decreased sensitivity to SNP in hypertensive vessels (EC50's: Control = 52 ± 11 nM; Hypertensive = 145 ± 64 nM, p<0.05 by ANOVA). DIP significantly enhanced relaxations to SNP in both groups (EC50's: Control = 1.1 ± 0.6 nM; Hypertensive = 28 ± 9 nM). A second series of experiments directly measured cGMP concentrations in PA by 125I RIA following stimulation with 1 μM SNP, 30 μM DIP, or both compounds and subsequent rapid freeze-clamping. Data are expressed as fmol cGMP/mg tissue weight, and compared by ANOVA: *p <0.05 vs. without SNP, †p<0.05 hypertensive vs. control. Table

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Further preliminary studies in hypertensive vessels (n=2 lambs) following pretreatment with 30 μM zaprinast indicate that cGMP increased from 8.3(NE+ZAP) to 56 fmol/mg (NE+ZAP+SNP). We conclude that both relaxations and cGMP accumulation to SNP are reduced in PA isolated from hypertensive lambs. DIP enhances relaxations and cGMP accumulation to SNP in PA isolated from both control and hypertensive lambs; although to a significantly greater degree in control vessels. Preliminary data indicate that an equimolar concentration of zaprinast may inhibit cGMP specific phosphodiesterase activity to a greater degree than dipyridamole. (Supported by AHA and NIH #HL 54705 and HL 28669)

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Steinhorn, R., Dukarm, R., Morin, F. et al. DIPYRIDAMOLE ENHANCES RELAXATIONS AND cGMP GENERATION TO NITRIC OXIDE IN LAMBS WITH PERSISTENT PULMONARY HYPERTENSION (PPHN). • 2090. Pediatr Res 39, 351 (1996) doi:10.1203/00006450-199604001-02114

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